Case PresentationSummer Pathology Seminar IAP 2012

Senec, Slovak Republic June 8-9, 2012

Fredrik Petersson MD, PhD

Associate Professor

Senior Consultant

Department of Pathology

National University of Singapore

National University Health System

Clinical History

• A 54 year old Chinese man developed progressively worsening stridor over the course of a few months.

• A CT scan revealed an subglottic laryngeal lesion measuring 1.5 cm located just below the vocal cords with partial obstruction of the lumen.

• A biopsy of the lesion was performed reported as a “soft tissue

sarcoma with smooth muscle differentiation” (not by me).

• Pre-operative chest x-rays, ultra-sound examination of the abdomen and MRI of the brain did not show any concurrent tumors.

• A total laryngectomy was performed.

2. Divider•Introducing new topic Histology

Cricoid

Tumor

Tumor

Lymph node

Tumor composed of two different components

Well circumscribed, unencapsulated

Slit-like blood vessels

Fascicles of spindle cells with bland nuclear features

Two sharply separated components

Cellular component – primitive appearing round cells

Focal nuclear atypia

Light Microscopic Features - Summary

• Biphasic non-encapsulated, well circumscribed tumor with no invasion into cartilage.

• (1) Moderately cellular spindle cell component with no significant nuclear atypia or mitotic activity.

• Presence of blood vessels.

• (2) A primitive, small round cell component featuring focal nuclear atypia (and mitotic activity).

• (1) and (2) sharply separated.

3. Divider•Introducing new topic Immunohistochemistry

SMA positive in both components

SMA spindle cells

SMA

SMA round cell component

SMA

Desmin

CD34 highlighted abundant vessels also in the cellular component

CD34 – spindle cell component

CD3 – Intratumoral T-cells

CD3

Immunohistochemistry - Summary

• Both components strongly positive for SMA and negative for desmin.

• Prominent vasculature (also in the primitive small round cell component).

• Intratumoral T-cells.

• Negative for S100 protein, CD34 and cytokeratins.

Diagnosis?

Additional History

• The patient had developed chronic renal failure and had a renal transplant 14 years prior to the development of the laryngeal tumor.

• The patient was on an immunosuppressive drugs; cyclosporine A and azathioprine.

Magic Bullet…

EBV (EBER) in situ hybridization

EBER – strongly positive in both components

EBER

EBER

EBER

Diagnosis: EBV associated Smooth Muscle Tumor

• I found that the patient had a previously diagnosed cutaneous angioleiomyoma.

• Which I retrieved and reviewed.

Working Up the Case…..

Fascicles of bland myoid cells

Medium sized blood vessels

Fascicles of myoid cells blending imperceptively with blood vessel

Morphology consistent withAngioleiomyoma/Vascular Leiomyoma

But…..

EBV (EBER) ISH – strongly positive

EBV associated SMT

Revised DX

EBV SMT - History

• In 1970 and 1971, smooth muscle tumors associated with immunosuppression were first reported.

• In the 1980s, there were steadily increasing numbers of patients with AIDS and transplant related immunosuppression and smooth muscle tumors, variably considered as leiomyomas or leiomyosarcomas.

• In 1994/95 the causative link between these tumors and Epstein-Barr virus was established.*

• Have also been associated with autoimmune diseases and common variable immunodeficiency syndrome .

* McClain KL et al. N Engl J Med. 1995 Jan 5;332(1):12-8.

* Prevot S et al. Virchows Arch. 1994;425(3):321-5.

EBV SMT – Anatomical Distribution

• EBV-SMTs have been described in a wide variety of anatomical locations and are frequently multifocal.

• Liver, spleen, gall bladder, tonsils, palate, nasopharynx, skin, pharynx, cribriform plate, orbita, larynx, mesentery, lung, iris, bone, skin, brain, meninges, spinal cord, common bile duct, myocardium, lymph nodes, adrenals, breast, pleura, urinary bladder, stomach, duodenum, gallbladder, spleen, small bowel, pericardium and bronchi.

EBV SMT – Anatomical Distribution

• The four most commonly reported sites in a review paper by Purgina et al on 64 cases of HIV-associated EBV- SMTs were CNS (brain and spinal cord; 20%), soft tissue (18%), lung (10%) and liver (9%).

EBV SMT – Morphological Spectrum

• The classical description of these tumors include: (1) A relatively monomorphic population of spindle cells arranged in short, interlacing fascicles and (2) A primitive round cell population that may appear intermixed with (1) or as separate/discrete nodules.

• Note: (2) is only present in approximately 50% of cases.

• A variably prominent vascular component is frequently present.

EBV SMT – Morphological Spectrum

• May be well circumscribed (with or without a capsule) or may display poor circumscription with destructive invasion into the surrounding tissues.

• The cellularity is variable and both fibrosis and hyaliniziation may be present.

• In most cases, an intratumoral infiltrate of T- lymphocytes is present.

• Mitotic activity is mostly low (<3/10 HPF), but may on occasion be brisk (with up to up to 23 mitotic figures/ 10 HPF reported ).

EBV SMT - Histogenesis

• The cell of origin for EBV-SMT is unclear.

• Some investigators have noted that minute EBV-SMTs have had a close relationship to the muscle cells of small caliber vessels.

• In one study the authors claimed to have noted dysplastic (?) changes of the cells in vessels walls, thus raising the possibility that this may represent a precursor lesion.

• On the other hand, the presence of EBV positive spindle cells within the vessel walls in the tumors, could well be attributed to invasion/replacement of the native smooth muscle cells of the vessel wall by tumor cells.

EBER -ISH

H-Caldesmon

EBV (EBER) ISH

EBV SMT: Immunohistochemitry

• EBV-SMTs express smooth muscle actin, h-caldesmon and muscle specific actin.

• Desmin is variably positive, but not uncommonly with a weak

and focal staining.

• Negativity for desmin is most consistently seen in the small primitive round cell component.

EBV SMT – Biology

• That EBV-SMTs are clonal proliferations has been firmly established in several studies.

• The frequent multifocality most likely represents different transforming events, i.e. separate tumors and not metastasis.

• There appears to be no relation between classical histopathological features of malignancy (nuclear atypia, mitotic activity etc) and prognosis (which appears more closely related to the site of involvement and the immune status of the patient).

EBV SMT - Differential Diagnoses

• The list of differential diagnoses is wide and varies with site and morphology of the particular EBV-SMT.

• Some entities that need to be considered are:

• Somatic or uterine leiomyomas/leiomyosarcomas • Cellular Schwannoma • MPNST• Meningioma• Inflammatory myofibroblastic tumor• Infective (mycobacterial, cryptococcal ) spindle cell pseudotumors• Inflammatory, pseudotumor-like, EBV+ follicular dendritic cell

sarcoma• Myofibroma/myofibromatosis• Myopericytoma• Glomangiopericytoma• GIST• SFT- Hemangiopericytoma• Endometrial stromal sarcoma with myoid differentiation.

• There exist no randomized controlled clinical trials and most of the data on this topic is based on case reports and small series.

• Surgical resection, reduction of immunosuppressive therapy and antiviral treatment are all modalities that have been used either in isolation or in various combinations.

• Cytotoxic chemotherapy and radiotherapy appear to be

ineffective.

EBV SMT - Treatment

EBV SMT - Treatment

• Few cases of AIDS associated EBV-SMT have shown stable disease and even regression of tumors with increased CD4 cell counts related to highly active antiretroviral therapy (HAART).

Thank you for your attention.

Questions?